This invention relates to novel and known benzoxazole derivatives, more particularly to a serotonin-5-HT3 receptor antagonist or a serotonin 5-HT3 receptor partial activator, which has been developed on the basis of the effective and selective action of said derivatives upon serotonin 5-HT3 receptors that are distributed in smooth muscles such as of digestive organs and the like and in central nervous system, intestinal nervous system and the like.
It has been revealed that serotonin 5-HT3 receptor antagonists can inhibit nausea and emesis as side effects caused by the use of cisplatin and the like carcinostatic agents and by radiation treatments, and several compounds thereof are now used in the clinical field. In addition to this, development on their use as digestive organ function controlling drugs has recently been examined.
The inventors of the present invention have already found that certain benzoxazole derivatives are possessed of serotonin 5-HT3 receptor antagonism (JP-A-6-345744; the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d).
When a compound having only serotonin 5-HT3 receptor antagonism is administered as a digestive organ function controlling drug, it can inhibit diarrhea but poses a problem of frequently causing constipation as a side effect.
In view of the above, it therefore becomes an object of the present invention to provide a serotonin 5-HT3 receptor partial activator which is possessed of not only serotonin 5-HT3 receptor antagonism but also serotonin 5-HT3 receptor activating action and is useful in getting rid of constipation side effect.
Using an evaluation test system in which serotonin 5-HT3 receptor antagonizing and activating actions are judged by a guinea pig excised ileum contraction action which can be used as an index of the serotonin 5-HT3 receptor activating action upon digestive organs, the inventors of the present invention have found that certain compounds among the benzoxazole derivatives disclosed in JP-A-345744 are possessed of serotonin 5-HT3 receptor partial activity. As a result of subsequent synthesis and evaluation studies, it was found that certain novel or known benzoxazole derivatives are possessed of not only serotonin 5-HT3 receptor antagonism but also serotonin 5-HT3 receptor activating action and are useful as strong serotonin 5-HT3 receptor partial activators. The present invention has been accomplished on the basis of these findings.
Accordingly, the gist of the present invention resides in the compounds of the following formulae (1) to (3): 
wherein R1 to R4 may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or optional two groups of R1 to R4 may be linked together to form a ring structure which is a 5- or 6-membered ring composed of carbon atoms alone or carbon atoms and 1 to 2 hetero atoms, selected from a cyclohexane ring, a benzene ring, a pyridine ring, a piperidine ring and a pyrrolidine ring; and Y represents a saturated or unsaturated, substituted or unsubstituted 4- to 8-membered hetero ring containing 1 to 3 nitrogen atoms as the ring constituting atoms and carbon atoms as the remaining atoms, which is selected from the group consisting of an azetidine ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, an imidazole ring, a pyrazinyl ring, a pyridazinyl ring, a triazole ring, a homopiperidine ring, a 1,4-diazacyclooctanyl ring and a 1,5-diazacyclooctanyl ring; 
wherein R1 to R4 may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R1 and R2 may be linked together to form a ring structure, namely a benzene ring, with the proviso that compounds in which all of R1 to R4 are hydrogen atoms are excluded; R5 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group; and m is an integer of 1 to 4; and 
wherein R1 to R4 may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of RI and R2 may be linked together to form a ring structure, namely a benzene ring, with the proviso that compounds in which all of R1 to R4 are hydrogen atoms are excluded; R5 and R6 may be the same or different from each other and each represents a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group; m is an integer of 1 to 4; and X- represents a halogen ion.
Further, the second aspect of the present invention resides in a serotonin 5-HT3 receptor partial activator containing, as an active ingredient, the compounds of any one of the formulae (1) to (3) or a compound represented by the formula (4) shown hereinafter, for example, for use in the treatment and prevention of functional disorders of digestive organs and diarrhea.
Other objects and advantages of the present invention will be made apparent as the description progresses.
In the aforementioned formula (1), examples of the ring structure represented by Y include an azetidine ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, an imidazole ring, a pyrazinyl ring, a pyridazinyl ring, a triazole ring, a homopiperidine ring, a 1,4-diazacyclooctanyl ring and a 1,5-diazacyclooctanyl ring. Preferably, Y is 4-pyridinyl group, 4-piperidinyl group, 4-homopiperidinyl group, 3-pyrrolidinyl group, 1-(1,4-diazacyclooctanyl) group or 1-(1,5-diazacyclooctanyl) group.
The substituent of Y is a group which is linked to a nitrogen atom of Y and selected from the group consisting of a straight or branched C1-C4 alkyl group and a straight or branched C2-C4 alkenyl group, and at least one hydrogen atom of the alkyl or alkenyl group may be substituted with a substituent group which may be selected from the group consisting of a hydroxyl group, a halogen atoms, a carbamoyl group, an amino group and a cyano group.
Particularly preferred compounds of the formula (2) are those in which R1 to R4 may be the same or different from one another and each represents a hydrogen atom, a halogen atom or a substituted or unsubstituted lower alkyl group, or two groups of R1 and R2 may be linked together to form a benzene ring; R5 is a substituted or unsubstituted lower alkyl group; and m is an integer of 2 or 3, with the proviso that compounds in which all of R1 to R4 are hydrogen atoms are excluded because such compounds are disclosed in JP-A-6-345744.
Definition
According to this specification, the alkyl or alkenyl as a group or a part of a group may be either straight chain or branched chain. Also in this specification, the term halogen atom means fluorine, chlorine, bromine or iodine atom.
Compounds of Formulae (1) to (3)
In the formulae (1) to (3), the lower alkyl group represented by any one of R1 to R6 is a C1-C4 alkyl group, and at least one hydrogen atom of the alkyl group may be substituted with a substituent group which may be selected from the group consisting of a halogen atom, a hydroxyl group, a carbamoyl group, an amino group and a cyano group.
The lower alkenyl group represented by any one of RI to R4 is a C2-C4 alkenyl group, and at least one hydrogen atom of the alkenyl group may be substituted with a substituent group which may be selected from the group consisting of a hydroxyl group, a halogen atoms, a carbamoyl group, an amino group and a cyano group.
Examples of the substituent group of the amino group represented by any one of R1 to R4 include those which are selected from the group consisting of a straight or branched C1-C4 alkyl group, a straight or branched C1-C4 alkylcarbonyl group, a straight or-branched C2-C4 alkenyl group and a benzylidene group which may have a phenyl group.
Use and Pharmaceutical Composition of the Compounds of Formulae (1) to (3) and a Compound of Formula (4)
According to the present invention, the compounds of formulae (1) to (3) and a compound represented by formula (4): 
(wherein m is an integer of 1 to 4) are possessed of serotonin 5-HT3 receptor antagonism and serotonin 5-HT3 receptor activating action. In consequence, they are useful as drugs for the treatment and prevention of diseases in which serotonin 5-HT3 is concerned. Examples of the serotonin 5-HT3-concerned diseases include emesis caused by the use of cisplatin and the like carcinostatic agents or by radiation treatments, as well as difficulty of gastrointestinal moving, irritable colon syndrome, headache, neuralgia, anxiety, depression, psychosis and the like.
In addition to the serotonin 5-HT3 receptor antagonism, the compounds of formulae (1) to (4) of the present invention also show serotonin 5-HT3 receptor partial activation action having serotonin 5-HT3 receptor activating action, so that they are particularly useful in the treatment and prevention of difficulty of gastrointestinal moving and irritable colon syndrome as a digestive organ function controlling drug which can inhibit diarrhea without causing constipation as a side effect.
The compounds of formulae (1) to (4) of the present invention can be used in the form of free bases or as pharmaceutically acceptable salts thereof. For example, the compounds of formulae (1), (2) and (4) can be administered in the form of an appropriate acid addition salt or quaternary ammonium salt. As such salts, pharmaceutically acceptable non-toxic salts can be exemplified. Preferred examples thereof include salts with hydrohalogenic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, inorganic acid salts such as sulfate, nitrate, phosphate, perchlorate, carbonate and the like, salts with carboxylic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, propionic acid, formic acid, malic acid and the like, salts with acidic amino acids such as aspartic acid, glutamic acid and the like and salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid and the like. In addition, the compound of formula (3) is administered as a salt of a halogen anion such as chlorine, bromine, iodine or the like represented by Xxe2x88x92 of the formula (3). Such salts of the compounds of formulae (1) to (4) show the same level of activities of the corresponding free bases. In consequence, the compounds represented by the general formulae (1) to (4), acid addition salts thereof and quaternary ammonium salts thereof are all included in the present invention.
Illustrative examples of more particularly preferred compounds of the present invention include, in the case of formula (1),
2-(4-pyridyl)benzoxazole,
2-(4-piperidyl)benzoxazole,
2-(4-piperidyl)-5-methylbenzoxazole,
5-chloro-2-(1-piperidyl)benzoxazole and
5,7-dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole, in the case of formula (2),
5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,
5,7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole,
6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,
6-methylamino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,
6-benzylideneamino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,
5-methyl-2-(1-piperazinyl)benzoxazole,
6-amino-5-chloro-2-(1-piperazinyl)benzoxazole,
6-dimethylamino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole,
5,7-dimethyl-2-(1-piperazinyl)benzoxazole,
2-(4-methyl-1-piperazinyl)-5-methylbenzoxazole,
2-(4-methyl-1-piperazinyl)-6-methylbenzoxazole,
2-(4-methyl-1-piperazinyl)-7-methylbenzoxazole,
2-(4-methyl-1-piperazinyl )-5,7-dichlorobenzoxazole,
2-(4-methyl-1-piperazinyl )naphtho[1,2-d]oxazole
2-(4-methyl-1-piperazinyl)-5-aminobenzoxazole,
2-(4-methyl-1-piperazinyl)-6-aminobenzoxazole,
2-(4-methyl-1-piperazinyl)-5-trifluoromethylbenzoxazole,
5-chloro-7-methyl-2-(4-methyl-1-piperazinyl )benzoxazole,
5-chloro-6, 7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole,
5,7-dichloro-6-methyl-2-(4-methyl-1-piperazinyl)benzoxazole,
5-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole,
5,7-dimethyl-2-(4-methyl-1-homopiperazinyl) benzoxazole,
5-chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole,
5-chloro-7-ethyl-2-(4-methyl-1-homopiperazinyl)benzoxazole,
5-chloro-6-methyl-2-(4-methyl-1-homopiperazinyl ) benzoxazole
2-(4-methyl-1-homopiperazinyl)naphtho[1,2-d]oxazole,
5-chloro-2-(4-methyl-1-homopiperazinyl)benzoxazole,
5-chloro-6-amino-2-(4-methyl-1-homopiperazinyl)benzoxazole,
5,7-dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole and
5,7-dimethyl-2-(4-methyl-1,4-diazacyclooctanyl)benzoxazole, in the case of formula (3),
1-allyl-1-methyl-4-(5-chlorobenzoxazol-2-yl)piperazinium iodide,
1-allyl-1-methyl-4-(5,7-dimethylbenzoxazol-2-yl)piperazinium iodide,
1-allyl-1-methyl-4-(6-amino-5-chlorobenzoxazol-2-yl)piperazinium bromide,
1-allyl-1-methyl-4-(5-methylbenzoxazol-2-yl)piperazinium bromide,
1-allyl-1-methyl-4-(5-trifluoromethylbenzoxazol-2-yl)piperazinium bromide,
1-allyl-1-methyl-4-(6-methylbenzoxazol-2-yl )piperazinium bromide,
1-allyl-1-methyl-4-(7-methylbenzoxazol-2-yl)piperazinium bromide,
1-allyl-1-methyl-4-(5,7-dichlorobenzoxazol-2-yl)piperazinium bromide and
1-allyl-1-methyl-4-(naphtho[1,2-d]benzoxazol-2-yl)piperazinium bromide, and in the case of formula (4),
2-(1-piperazinyl)benzoxazole.
A pharmaceutical composition which comprises the compound of the present invention as its active ingredient can be administered to human-and animals other than human through the route of administration of either oral or parenteral (for example, intravenous injection, intramuscular injection, subcutaneous administration, percutaneous administration and the like).
In consequence, the pharmaceutical composition which contains the compound of the present invention as its active ingredient is made into appropriate dosage forms depending on the route of administration. Illustrative examples of oral dosage forms include tablets, capsules, powders, granules, syrups and the like, and those of parenteral dosage forms include intravenous, intramuscular and the like injections, rectal administration preparations, oleaginous suppositories, aqueous suppositories and the like. These various types of preparations can be produced in the usual way making use of generally used fillers, disintegrators, binders, lubricants, coloring agents and the like.
Illustrative examples of non-toxic fillers which can be used include lactose, glucose, corn starch, sorbitol, crystalline cellulose and the like, those of disintegrators include starch, sodium alginate, gelatin, calcium carbonate, calcium citrate, dextrin and the like, those of binders include dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, acacia, hydroxypropyl cellulose, polyvinyl pyrrolidone and the like and those of lubricants include talc, magnesium stearate, polyethylene glycol, hardened oil and the like.
In the case of injections, a buffer, a pH adjusting agent, an stabilizing agent and the like may be added as occasion demands.
Amount of the drug of the present invention to be contained in the pharmaceutical composition varies depending on the dosage form, but is generally from 0.05 to 50% by weight, preferably from 0.1 to 20% by weight, based on the total composition.
Its dose is optionally decided in each case by taking age, body weight, sex, difference in diseases, degree of symptoms and the like of each patient into consideration, but is generally from 0.5 to 1,000 mg, preferably from 1 to 300 mg, per adult per day when used as a digestive organ function controlling drug, and the daily dose may be administered once a day or by dividing it into several doses per day.
Production of the Compound of Formula (1)
The compound of formula (1) of the present invention can be produced by various methods, but it may be produced preferably by the following two typical methods in the case of a compound in which a carbon atom of Y is linked to the benzoxazole ring. 
A compound represented by the formula-(6) (in the formula, R1, R2, R3 and R4 are as defined in the formula (1)) is allowed to react with 1 to 10 equivalents of an aldehyde represented by the formula (7) (in the formula, Y is as defined in the formula (1)), thereby obtaining, among the intended compounds of formula (1) (in the formula, R1, R2, R3, R4 and Y are as defined in the foregoing), a compound in which a carbon atom of Y is linked to the benzoxazole ring.
Alternatively, a compound represented by the formula (6) (in the formula, R1, R2, R3 and R4 are as defined in the formula (1)) is allowed to react with 1 to 10 equivalents of a carboxylic acid represented by the formula (8) (in the formula, Y is as defined in the formula (1)) to obtain the compound of formula (9) (in the formula, R1, R2, R3, R4 and Y are as defined in the formula (1)) which is then subjected to cyclization, thereby obtaining, among the intended compounds of formula (1) (in the formula, R1, R2, R3, R4 and Y are as defined in the foregoing), a compound in which a carbon atom of Y is linked to the benzoxazole ring.
In the case of a compound in which a nitrogen atom of Y is linked to the benzoxazole ring, it can be produced preferably by the following method. 
A compound represented by the formula (10) (in the formula, R1, R2, R3 and R4 are as defined in the formula (1) and Z represents a halogen atom or a thiol group) is allowed to react with 1 to 50 equivalents of a compound of nitrogen-containing ring structure represented by the formula (11) (in the formula, Y is as defined in the formula (1)), thereby obtaining, among the intended compounds of formula (1) (in the formula, R1, R2, R3, R4 and Y are as defined in the foregoing), a compound in which a nitrogen atom of Y is linked to-the benzoxazole ring.
Production of the Compounds of Formulae (2) and (4)
The compound represented by the formula (2) or (4) can be produced preferably by the following two typical methods. 
A compound represented by the formula (12) (in the formula, R1, R2, R3 and R4 are as defined in the formula (2) and Z is a halogen atom or a thiol group) is allowed to react with 1 to 50 equivalents of an N-substituted alicyclic diamine represented by the formula (13) (in the formula, R5 is a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group and m is as defined in the formula (2)), thereby obtaining the intended compound of formula (2) (in the formula, R1, R2, R3, R4 and m are as defined in the foregoing and R5 is a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group).
Alternatively, a compound represented by the formula (12) (in the formula, R1, R2, R3 and R4 are all hydrogen atoms or as defined in the formula (2) and Z is a halogen atom or a thiol group) is allowed to react with an alicyclic diamine represented by the formula (14) (in the formula, m is as defined in the formula (2)) to convert into the compound of formula (15) (in the formula, R1, R2, R3 and R4 are all hydrogen atoms or as defined in the formula (2) and m is as defined in the formula (2)) which is a compound of the formula (2) in which R5 is hydrogen atom or a compound of the formula (4), subsequently allowing the resulting compound to react with 1 to 5 equivalents of a compound represented by the formula (16) (in the formula, R5 is a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group and X is a halogen atom), thereby obtaining the intended compound of formula (2) (in the formula, R1, R2, R3, R4 and m are as defined in the formula (2) and R5 is a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted-lower alkenyl group).
Production of the Compound of Formula (3)
The compound represented by the formula (3) can be produced preferably by the following method. 
That is, a compound represented by the formula (2) (in the formula, R1, R2, R3, R4 and m are as defined in the formula (2) and R5 is a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group) is allowed to react with 1 to 10 equivalents of a compound represented by the formula (17) (in the formula, R6 is as defined in the formula (3) and X is a halogen atom), thereby obtaining the intended compound of formula (3) (in the formula, R1, R2, R3, R4, R5, R6 and m are as defined in the formula (3) and Xxe2x88x92 is a halogen ion).
The reaction of compound (6) with compound (7) is quickly completed when they are allowed to react with each other in an organic acid such as acetic acid, trifluoroacetic acid or the like at 0 to 150xc2x0 C. for 1 to 12 hours.
The compound (9) can be obtained easily when the reaction of compound (6) with compound (8) is carried out in a solvent such as DMF or the like at 0 to 150xc2x0 C. for 1 to 12 hours in the presence of a chlorination agent such as thionyl chloride or the like or a condensing agent such as DCC or the like. Also, cyclization of the compound (9) is quickly completed within 1 to 24 hours when it is allowed to undergo the reaction at 50 to 150xc2x0 C. in DMF or the like solvent in the presence of PPTS or the like acid catalyst or when it is heated at 50 to 200xc2x0 C. together with polyphosphoric acid without solvent.
The reaction of compound (10) with compound (11) is quickly completed when they are allowed to react with each other without solvent or in DMF or the like solvent in the presence of triethylamine or the like alkylamine base at 0 to 150xc2x0 C. for 1 to 12 hours.
The reaction of compound (12) with compound (13) or (14) is quickly completed when they are allowed to react with each other without solvent or in DMF or the like solvent in the presence of triethylamine or the like alkylamine base at 0 to 150xc2x0 C. for 1 to 12 hours.
Formation of the compound (2) or (3) by the reaction of compound (15) with compound (16) or the reaction of compound (2) with compound (17) can be effected easily when they are allowed to react with each other in DMF or the like solvent at 0 to 150xc2x0 C. for 1 to 12 hours.
The following reference examples, inventive examples and test examples are provided to further illustrate the present invention. It is to be understood, however, that the examples are for purpose of illustration only and are not intended as a definition of the limits of the invention, and therefore that various variations and modifications can be made within the scope of the invention as a matter of course. The NMR data in the examples are 8 values based on TMS internal standard when measured using 400 MHz NMR.